Obesity is a major health problem. A key cause of obesity is increased food intake and decreased energy expenditure. The CNS receives information from the periphery relevant to an individual's energy balance through metabolic, neural, and endocrine signals. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays essential roles in the regulation of energy balance in the CNS by promoting decreased food intake and increased energy expenditure. There is increasing evidence that regulation of energy balance and body weight is not the same for both genders. BDNF neurons are downstream mediators of the melanocortinergic system, and they directly receive input from the proopiomelanocortin (POMC) neurons that are activated by an adiposity signal leptin. Females have greater sensitivity to central leptin than males, suggested by a greater anorexic effect of central leptin administration in females. Thus it is possible that sex difference exists in the leptin-POMC downstream BDNF system. The gender difference in BDNF signaling in energy balance has been suggested from studies using transgenic mice with dysfunctional BDNF system. Decreasing BDNF action by conditionally deleting the BDNF gene or reducing expression of its specific receptor tropomyosin- related kinase B (TrkB) leads to hyperphagia and obesity, with females having more potent phenotypes and developing more severe obesity than males, suggesting that females are more sensitive to the loss of BDNF signaling and thus a functional BDNF system is more crucial in the regulation of energy homeostasis in females. We previously described the phenotype of mice lacking leptin receptors selectively in POMC neurons and identified sex differences in energy balance regulation. Mice with disrupted leptin-POMC signaling exhibit gender-specific physiological mechanisms to reach similar level of obesity;male mice consume more calories while female mice burn fewer calories. The interesting finding is that both males and females with disturbed leptin-POMC signaling show increased adiposity but achieve this through distinct physiological mechanisms. Given these findings we hypothesize that since BDNF system is a direct downstream element of leptin-POMC signaling, the decreased body weight, decreased energy intake, and increased energy expenditure induced by BDNF would be regulated differentially between genders. This R15 proposal aims to elucidate and identify sex differences in the regulation of the BDNF system with the long term goal to generate data that will be useful in developing gender-specific therapeutics to treat or prevent obesity. The effect of BDNF on food intake and energy expenditure has never been thoroughly examined in female rats. Our preliminary data revealed gender-specific effects of central BDNF on food intake and energy expenditure. Males responded with a decreased food intake to a lower centrally injected dose of BDNF than females. Females, but not males, significantly increased their energy expenditure following administration of a low dose of BDNF. These preliminary findings point to very distinct physiological gender-specific mechanisms of body weight regulation. This R15 proposal aims to determine the underlying mechanisms of the sex-specific responses to BDNF treatment. We will first investigate the hypothesis that gonadal hormones modulate the activity of the BDNF/TrkB signaling. We further hypothesize that estrogen enhances the BDNF-induced increase in energy expenditure and that sex differences in energy expenditure may be due to different neural substrates activated by BDNF. By utilizing behavioral, physiological, and molecular techniques, we will examine the relative contributions to feeding and energy expenditure of BDNF and its receptor TrkB in intact and gonadectomized male and female rats using specific TrkB agonist and blocker. The large difference between males and females in the regulation of energy homeostasis suggests the potential need for gender-specific strategies to produce therapeutic weight loss. The role of altered energy intake and expenditure and the underlying mechanism of sex differences in energy homeostasis have not been unequivocally discerned. This R15 proposal will provide important new information about sex differences in response to BDNF treatment. Such information is invaluable for identifying gender- specific biological targets for intervention to prevent or treat obesity. In addition, illuminating how gonadal hormones mediate central BDNF signaling systems to regulate caloric ingestion and energy expenditure will provide critical information on therapeutic targets for postmenopausal women. PUBLIC HEALTH RELEVANCE: As the prevalence of overweight and obesity is rising, the incidence of type 2 diabetes, cardiovascular disease, and some types of cancer is increasing at a similar alarming rate. It is essential that novel therapeutic and prevention strategies for obesity are developed and this can only be achieved by attaining a clear understanding of the factors contributing to energy balance. The CNS receives information from the periphery relevant to an individual's energy balance through metabolic, neural, and endocrine signals. Understanding the neuroendocrine (brain-hormone) control of body weight regulation is critical before specific treatments can be identified. A key cause of obesity is increased food intake and decreased energy expenditure. Brain-derived neurotrophic factor (BDNF) is an essential neuropeptide that plays an integral role in energy balance in the CNS via promoting decreased food intake and increased energy expenditure. There is increasing evidence that the regulation of body weight is not the same for both genders. The role of altered energy intake and expenditure and the underlying mechanism of sex difference in energy homeostasis have not been unequivocally discerned. While it is obvious that differences in gonadal hormones play a key role in regulating differences in body weight between males and females, illuminating how these hormones influence specific biological systems that regulate caloric ingestion and energy expenditure is critical to future therapies. The results obtained from the studies proposed in this R15 proposal will elucidate and identify sex differences in the regulation of the BDNF signaling system with the long term goal to generate data that will be useful in developing gender-specific therapeutics to treat or prevent obesity.